Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development

ABSTRACT Biliary atresia (BA) is a neonatal liver disease characterized by progressive fibroinflammatory obliteration of both intrahepatic and extrahepatic bile ducts. The etiologies of BA remain largely unknown, but rotavirus infection has been implicated at least for a subset of patients, and this...

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Autores principales:	Sunrui Chen, Pengfei Li, Yining Wang, Yuebang Yin, Petra E. de Ruiter, Monique M. A. Verstegen, Maikel P. Peppelenbosch, Luc J. W. van der Laan, Qiuwei Pan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	biliary atresia rotavirus infection human organoids Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/745094e524b741e6866274ae7abcbfc8
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spelling	oai:doaj.org-article:745094e524b741e6866274ae7abcbfc82021-11-15T15:56:45ZRotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development10.1128/mBio.01968-202150-7511https://doaj.org/article/745094e524b741e6866274ae7abcbfc82020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01968-20https://doaj.org/toc/2150-7511ABSTRACT Biliary atresia (BA) is a neonatal liver disease characterized by progressive fibroinflammatory obliteration of both intrahepatic and extrahepatic bile ducts. The etiologies of BA remain largely unknown, but rotavirus infection has been implicated at least for a subset of patients, and this causal relation has been well demonstrated in mouse models. In this study, we aim to further consolidate this evidence in human biliary organoids. We obtained seven batches of human biliary organoids cultured from fetal liver, adult liver, and bile duct tissues. We found that these organoids are highly susceptible and support the full life cycle of rotavirus infection in three-dimensional culture. The robust infection triggers active virus-host interactions, including interferon-based host defense mechanisms and injury responses. We have observed direct cytopathogenesis in organoids upon rotavirus infection, which may partially recapitulate the development of BA. Importantly, we have demonstrated the efficacy of mycophenolic acid and interferon alpha but not ribavirin in inhibiting rotavirus in biliary organoids. Furthermore, neutralizing antibody targeting rotavirus VP7 protein effectively inhibits infection in organoids. Thus, we have substantiated the causal evidence of rotavirus inducing BA in humans and provided potential strategies to combat the disease. IMPORTANCE There is substantial evidence indicating the possible involvement of rotavirus in biliary atresia (BA) development, at least in a subset of patients, but concrete proof remains lacking. In a mouse model, it has been well demonstrated that rotavirus can infect the biliary epithelium to cause biliary inflammation and obstruction, representing the pathogenesis of BA in humans. By using recently developed organoids technology, we now have demonstrated that human biliary organoids are susceptible to rotavirus infection, and this provokes active virus-host interactions and causes severe cytopathogenesis. Thus, our model recapitulates some essential aspects of BA development. Furthermore, we have demonstrated that antiviral drugs and neutralizing antibodies are capable of counteracting the infection and BA-like morphological changes, suggesting their potential for mitigating BA in patients.Sunrui ChenPengfei LiYining WangYuebang YinPetra E. de RuiterMonique M. A. VerstegenMaikel P. PeppelenboschLuc J. W. van der LaanQiuwei PanAmerican Society for Microbiologyarticlebiliary atresiarotavirus infectionhuman organoidsMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	biliary atresia rotavirus infection human organoids Microbiology QR1-502
spellingShingle	biliary atresia rotavirus infection human organoids Microbiology QR1-502 Sunrui Chen Pengfei Li Yining Wang Yuebang Yin Petra E. de Ruiter Monique M. A. Verstegen Maikel P. Peppelenbosch Luc J. W. van der Laan Qiuwei Pan Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development
description	ABSTRACT Biliary atresia (BA) is a neonatal liver disease characterized by progressive fibroinflammatory obliteration of both intrahepatic and extrahepatic bile ducts. The etiologies of BA remain largely unknown, but rotavirus infection has been implicated at least for a subset of patients, and this causal relation has been well demonstrated in mouse models. In this study, we aim to further consolidate this evidence in human biliary organoids. We obtained seven batches of human biliary organoids cultured from fetal liver, adult liver, and bile duct tissues. We found that these organoids are highly susceptible and support the full life cycle of rotavirus infection in three-dimensional culture. The robust infection triggers active virus-host interactions, including interferon-based host defense mechanisms and injury responses. We have observed direct cytopathogenesis in organoids upon rotavirus infection, which may partially recapitulate the development of BA. Importantly, we have demonstrated the efficacy of mycophenolic acid and interferon alpha but not ribavirin in inhibiting rotavirus in biliary organoids. Furthermore, neutralizing antibody targeting rotavirus VP7 protein effectively inhibits infection in organoids. Thus, we have substantiated the causal evidence of rotavirus inducing BA in humans and provided potential strategies to combat the disease. IMPORTANCE There is substantial evidence indicating the possible involvement of rotavirus in biliary atresia (BA) development, at least in a subset of patients, but concrete proof remains lacking. In a mouse model, it has been well demonstrated that rotavirus can infect the biliary epithelium to cause biliary inflammation and obstruction, representing the pathogenesis of BA in humans. By using recently developed organoids technology, we now have demonstrated that human biliary organoids are susceptible to rotavirus infection, and this provokes active virus-host interactions and causes severe cytopathogenesis. Thus, our model recapitulates some essential aspects of BA development. Furthermore, we have demonstrated that antiviral drugs and neutralizing antibodies are capable of counteracting the infection and BA-like morphological changes, suggesting their potential for mitigating BA in patients.
format	article
author	Sunrui Chen Pengfei Li Yining Wang Yuebang Yin Petra E. de Ruiter Monique M. A. Verstegen Maikel P. Peppelenbosch Luc J. W. van der Laan Qiuwei Pan
author_facet	Sunrui Chen Pengfei Li Yining Wang Yuebang Yin Petra E. de Ruiter Monique M. A. Verstegen Maikel P. Peppelenbosch Luc J. W. van der Laan Qiuwei Pan
author_sort	Sunrui Chen
title	Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development
title_short	Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development
title_full	Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development
title_fullStr	Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development
title_full_unstemmed	Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development
title_sort	rotavirus infection and cytopathogenesis in human biliary organoids potentially recapitulate biliary atresia development
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/745094e524b741e6866274ae7abcbfc8
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Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development

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